This invention relates to manganese complexes of various polyether antibiotics as new compositions of matter, processes for making these manganese complexes, and to processes for the administration of manganese complexes of polyether antibiotics to food-producing animals such as cattle, sheep, swine, and poultry to promote growth, to enhance feeding efficiency, and/or to combat coccidial infections. The subject manganese complexes of polyether antibiotics may be administered orally as feed additives in the crude form, or may be first purified, and administered as boluses, parenterally as injections, or as subcutaneous implants.
Cardiovascular function in animals may be improved by administering manganese complexes of polyether antibiotics. The manganese complexes of polyether antibiotics formed in fermentation beers as described herein may be purified further for pharmaceutical use in humans.
Polyether antibiotics can be generally characterized as carboxylic acid ionophores which can be produced by growing Streptomyces type microorganisms in suitable nutrient media. These polyether antibiotics have a basic structure generally consisting essentially of the elements oxygen, hydrogen and carbon (and sometimes nitrogen) and have a molecular weight in the range of about 300 to about 1800, most often from about 400 to about 1200. They have low solubility in water, are generally soluble in low molecular weight alcohols, ethers, and ketones; and have at least one, and usually one or two, carboxylic acid groups. A generally comprehensive review of this class of antibiotics is set forth in Westley, Adv. Appl. Microbiology 22, 177-233 (1977). As is mentioned therein, at least twenty different polyether antibiotics were known at the time the article was written. Since then, additional polyether antibiotics have been discovered.
In Westley (op. cit.), the known polyether antibiotics are divided into four separate classes based on the ability of the particular antibiotic to effect the transport of monovalent and divalent cations and based on the chemical structure of the particular antibiotic. Westley's classification system is adopted herein.
Westley defined Class 1a as monovalent polyether antibiotics. In addition, the Class 1a polyether antibiotics have a generally linear configuration, i.e., the carboxylic portion of the polyether molecule is attached either directly or indirectly to a terminal ring structure, and include about four to six tetrahydropyran and/or -furan structures, and up to six total ring structures. Class 1a includes monensin, laidlomycin, nigericin, grisorixin, salinomycin, narasin, lonomycin, X-206, SY-1, noboritomycins A and B, mutalomycin and alborixin. Class 1a antibiotics may also be described as "linear monovalent polyether antibiotics".
According to Westley's system, monovalent monoglycoside polyether antibiotics belong to Class 1b. These polyether antibiotics belong to Class 1b. These polyether antibiotics include a glycoside type structure, more specifically, a 2,3,6-trideoxy-4-O-methyl-D-erythrohexapyranose moiety, which is attached to the polyether molecule such that a non-linear type molecule is formed, i.e., the carboxylic portion of the polyether molecule is attached either directly or indirectly to a non-terminal ring structure or the molecule has a side chain ring structure, e.g., a 2,3,6-trideoxy-4-O-methyl-D-erythrohexapyranose moiety. The polyether antibiotics of this class usually contain about six or seven tetrahydropyran and/or -furan structures.
Class 2a antibiotics as defined by Westley are divalent polyethers, and have a generally linear configuration. They may contain from about two to about three tetrahydropyran and/or -furan structures, and up to about three total ring structures. Nitrogen atoms are not present in the Class 2a molecules. Included within Class 2a are lasalocid and lysocellin. The Class 2a polyether antibiotics are hereinafter sometimes designated "non-nitrogen containing divalent polyether antibiotics".
Class 2b in Westley's system are divalent pyrrole polyethers. In contrast to the other classes, the Class 2b antibiotics contain one or more nitrogen atoms.
Lasalocid is included in Class 2a as defined by Westley. Lasalocid was discovered by Julius Berger et al in media fermented with a Streptomyces microorganism isolated from a sample of soil collected at Hyde Park, Mass. [Cf. Berger et al, J. Am. Chem. Soc. 73, 5295-8 (1951)]. Originally this material was known by the code name X-537A. About 1969 lasalocid was found to possess coccidiostatic activity. Later this activity was established for monensin, nigericin, salinomycin, and narasin all of which belong to Class 1a.
The polyether antibiotics have usually been recovered and employed in the form of their sodium salts. For example, a process for recovering lasalocid from its fermentation broth is disclosed in the Berger et al article (op. cit.). In this process, the antibiotic or its alkali metal salts are extracted into various organic solvents with subsequent evaporation of the solvents in a multi-step operation.
A process for the recovery of carriomycin from fermentation beer is described by Imada et al in J. Antibiotics 31, 7-14 (1978). In the disclosed process, fermented beer containing the carriomycin antibiotic was adjusted in pH with concentrated NaOH and acetone was then added. After stirring the mixture for 1 hour at room temperature, mycelia were filtered off and extracted again with acetone. The extracts were combined and concentrated in a vacuum until no acetone remained. The concentrated aqueous solution was extracted twice with equal volumes of ethyl acetate, followed by drying with anhydrous Na.sub.2 SO.sub.4. The extracts were concentrated in a vacuum and passed through a column of activated charcoal, then the column was washed with ethyl acetate. The fractions active against Staphylococcus aureus FDA 209P were combined and the solvent was evaporated. To the oily residue was added n-hexane. The resultant solid material was collected by filtration and crystallized from aqueous acetone. On recrystallization from aqueous acetone, crystals of the mixed sodium and potassium salts of carriomycin were obtained, the mixture was dissolved in aqueous acetone, and the solution was extracted twice with equal volumes of ethyl acetate. The extracts were dried with anhydrous Na.sub.2 SO.sub.4 and concentrated to dryness in a vacuum. The resultant crystalline powder was recrystallized from aqueous acetone to yield carriomycin free acid.
As is apparent from the above example, such processes can be quite complicated and can require the use of relatively large quantities of various organic solvents, at least some of which may be quite expensive. In addition, such solvent recovery processes inevitably will suffer antibiotic yield losses as well as losses of the various organic solvents used in the process. There is thus a continuing need for antibiotic preparation and recovery processes which effectively and efficiently produce polyether antibiotics in a form suitable for use as feed additives.